Method of treating cardiovascular events using colchicine concurrently with an antiplatelet agent

ABSTRACT

Methods of treating and/or preventing a cardiovascular event in a patient, the method comprising orally administering a colchicine to a patient who is receiving concurrent treatment with at least one antiplatelet agent, thereby treating and/or preventing the cardiovascular event in the patient are provided.

RELATED APPLICATION(S)

This application is a continuation of U.S. patent application Ser. No.16/229,504, filed Dec. 21, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/663,148, filed Jul. 28, 2017, which is acontinuation of U.S. patent application Ser. No. 14/603,049, filed Jan.22, 2015, which is a continuation-in-part of PCT Application No.PCT/AU2013/001261, filed Nov. 1, 2013, which claims the benefit ofAU2012/904828, filed Nov. 2, 2012 and AU2012/904868, filed Nov. 5, 2012,the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Colchicine, chemical name (−)-N-[(7S,12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide,is an alkaloid found in extracts of Colchicum autumnale, Gloriosasuperba, and other plants. It is a microtubule-disrupting agent used inthe treatment of conditions that may be treated, relieved or preventedwith anti-inflammatory treatment.

Colchicine is well recognized as a valid therapy in acute flares ofgouty arthritis, familial Mediterranean fever (FMF), Behçet's disease.It has also been used to treat many inflammatory disorders prone tofibrosis. In the recent past, colchicine has been proposed to beeffective in therapy in cardiovascular diseases.

In particular, colchicine has been proposed as a first treatment optionfor recurrent pericarditis (class I indication) and optional for acutepericarditis (class Ha indication) in the 2004 European guidelines onthe management of pericardial diseases (Maisch et al., Guidelines on theDiagnosis and Management of Pericardial Diseases, Eur Heart J., 2004,25, 916-928).

Imazio et al. (Circulation, 2005, 112 (13), 2012-2016) showed thatcolchicine was effective for the treatment and the prevention ofrecurrent pericarditis in a prospective, randomized, open-label designedstudy of 120 patients with a first episode of acute pericarditis(idiopathic, viral, postpericardiotomy syndromes, and connective tissuediseases), who were randomly assigned to conventional treatment withaspirin or conventional treatment plus colchicine (1.0 to 2.0 mg for thefirst day and then 0.5 to 1.0 mg/day for 3 months). The primary endpoint was recurrence rate, which was significantly reduced from 32.3%down to 10.7% at 18 months in the colchicine group (p=0.004).

Further, the same group showed that colchicine could be efficient afterconventional treatment failure to manage acute pericarditis (Imazio atal., Arch InternMed, 2005, 165 (17), 1987-91). In a prospective,randomized, open-label design, 84 consecutive patients with a firstepisode of recurrent pericarditis were randomly assigned to receiveconventional treatment with aspirin alone or conventional treatment pluscolchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6months). The primary end point was the recurrence rate, which wassignificantly decreased in the colchicine group (actuarial rates at 18months were 24.0% vs 50.6% with conventional treatment).

It has also been shown that colchicine is effective for secondaryprevention of recurrent pericarditis Imazio et al., Ann. Intern. Med.,2011, 155 (7), 409-14). Colchicine has also been proposed to reducepostpericardiotomy reactions revealed as pericarditis (Imazio et al.,Am. Heart J., 2011, 162 (3), 527-532; Meurin and Tabet, Arch.Cardiovasc. Dis., 2011, 104 (8-9), 425-427).

Colchicine for the treatment of post-pericardiotomy syndrome (PPS) wastested for the first time in a preliminary prospective, open-label,randomized trial of colchicine (1.5 mg/day) compared with placebobeginning on the third post-operative day in 163 patients who underwentcardiac surgery (Finkelstein et al., Herz, 2002 27, 791-194).

The effectiveness of colchicine for the prevention of PPS has also beenshown in a multicentre, double-blind, randomized trial, in which 360patients (mean age 65.7+12.3 years, 66% males), 180 in each treatmentarm, were randomized to receive placebo or colchicine (1.0 mg twicedaily for the first day followed by a maintenance dose of 0.5 mg twicedaily for 1 month in patients ≥70 kg, and halved doses for patients, 70kg or intolerant to the highest dose) on the third post-operative day(Imazio et al., European Heart Journal, 2010, 31, 2749-2754).

In patients with atherosclerotic vascular disease, the diseased vesselwall is subject to injurious forces that promote plaque build-up andinstability that may lead to coronary occlusion resulting in heartattack, ischemic stroke and sudden death. The response to injury withinthe diseased vessel is dependent on the architecture and content ofatherosclerotic plaques. Lipid-rich plaques with a neo-vascular base areparticularly susceptible to the effect of injury, which may leave themvulnerable to neutrophil infiltration. Neutrophils that enter theinterstitial space may become activated upon exposure to the plaquecontents, inciting an aggressive inflammatory response that mayaccelerate plaque instability increasing the risk of plaque enlargementand rupture and hence increasing the risk of clinical events.

Despite routine use of anti-platelet and statin therapy, patients withatherosclerotic vascular disease continue to be at risk ofcardiovascular events, possibly because these treatments fail to targetsome of the inflammatory pathways implicated in the disease.

A number of additional treatments exist for the prevention or reductionin risk of coronary heart disease, including: antiplatelet agents(besides aspirin), anticoagulants, angiotensin-converting-enzymeinhibitors (ACE1s); aldosterone receptor antagonists (ARAB);beta-blockers calcium channel blockers and/or nitrates.

However, many of these treatments are recommended for acute conditionsand do not address or provide for a long-term reduction incardiovascular events in patients with clinically stable atheroscleroticvascular disease.

The present invention seeks to overcome, or at least ameliorate, one ormore of the deficiencies of the prior art mentioned above, or to providethe consumer with a useful or commercial choice.

SUMMARY OF THE INVENTION

According to aspects of the invention illustrated herein, there isprovided a method of treating and/or preventing a cardiovascular eventin a patient, the method comprising administering a compositioncomprising an effective amount of colchicine to a patient who isreceiving concurrent treatment with at least one antiplatelet agent,thereby treating and/or preventing the cardiovascular event in thepatient.

According to embodiments of the invention, the patient has a coronarydisease. According to embodiments of the invention, the coronary diseaseis a clinically stable coronary disease. According to embodiments of theinvention, the cardiovascular event is acute coronary syndrome,out-of-hospital cardiac arrest, and/or noncardioembolic ischemic stroke.According to embodiments of the invention, the antiplatelet agent isaspirin. According to embodiments of the invention, colchicine isincluded in an amount of 0.6 mg. According to embodiments of theinvention, colchicine is included in an amount of 0.5 mg.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

For the purposes of this invention, the term “colchicine” includescolchicine or any pharmaceutically acceptable salts thereof.

“Pharmaceutically acceptable” means that which is generally safe,non-toxic and neither biologically nor otherwise undesirable andincludes that which is acceptable for veterinary use as well as humanpharmaceutical use.

“Pharmaceutically acceptable salts” includes derivatives of colchicine,wherein the colchicine is modified by making acid or base addition saltsthereof, and further refers to pharmaceutically acceptable solvates,including hydrates, and co-crystals of such compounds and such salts.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid addition salts of basic residuessuch as amines; alkali or organic addition salts of acidic residues; andthe like, and combinations comprising one or more of the foregoingsalts. The pharmaceutically acceptable salts include non-toxic salts andthe quaternary ammonium salts of the colchicine. For example, non-toxicacid salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric andthe like; other acceptable inorganic salts include metal salts such assodium salt, potassium salt, cesium salt, and the like; and alkalineearth metal salts, such as calcium salt, magnesium salt, and the like,and combinations comprising one or more of the foregoing salts.Pharmaceutically acceptable organic salts includes salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic,esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC—(CH2)n-COOHwhere n is 0-4, and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, and thelike; and amino acid salts such as arginate, asparaginate, glutamate,and the like; and combinations comprising one or more of the foregoingsalts; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′ dibenzylethylenediamine salt, and the like;and amino acid salts such as arginate, asparaginate, glutamate, and thelike; and combinations comprising one or more of the foregoing salts.All forms of such derivatives of colchicine are contemplated herein,including all crystalline, amorphous, and polymorph forms. Specificcolchicine salts include colchicine hydrochloride, colchicinedihydrochloride, and co-crystals, hydrates or solvates thereof.

“Pharmacokinetic parameters” describe the in vivo characteristics of anactive agent (or a metabolite or a surrogate marker for the activeagent) over time, such as plasma concentration (C), Cmax, Cn, C24, Tmax,and AUC. “Cmax” is the measured plasma concentration of the active agentat the point of maximum, or peak, concentration. “Cmin” is the measuredplasma concentration of the active agent at the point of minimumconcentration. “Cn” is the measured plasma concentration of the activeagent at about n hours after administration. “C24” is the measuredplasma concentration of the active agent at about 24 hours afteradministration. The term “Tmax” refers to the time at which the measuredplasma concentration of the active agent is the highest afteradministration of the active agent. “AUC” is the area under the curve ofa graph of the measured plasma concentration of an active agent vs.time, measured from one time point to another time point. For exampleAUCO-t is the area under the curve of plasma concentration versus timefrom time 0 to time t, where t can be the last time point withmeasurable plasma concentration for an individual formulation. TheAUCO-∞ or AUCO-INF is the calculated area under the curve of plasmaconcentration versus time from time 0 to time infinity. In steady-statestudies, AUCO-τ is the area under the curve of plasma concentration overthe dosing interval (i.e., from time 0 to time r (tau), where tau is thelength of the dosing interval. Other pharmacokinetic parameters are theparameter Ke or Kel, the terminal elimination rate constant calculatedfrom a semi-log plot of the plasma concentration versus time curve; t½the terminal elimination half-life, calculated as 0.693/Kel; CL/Fdenotes the apparent total body clearance after administration,calculated as Total Dose/Total AUC∞; and Varea/F denotes the apparenttotal volume of distribution after administration, calculated as TotalDose/(Total AUC∞×Kel).

“Efficacy” means the ability of an active agent administered to apatient to produce a therapeutic effect in the patient.

“Bioavailability” means the extent or rate at which an active agent isabsorbed into a living system or is made available at the site ofphysiological activity. For active agents that are intended to beabsorbed into the bloodstream, bioavailability data for a givenformulation may provide an estimate of the relative fraction of theadministered dose that is absorbed into the systemic circulation.“Bioavailability” can be characterized by one or more pharmacokineticparameters.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, creams, ointments, suppositories,inhalable forms, transdermal forms, and the like.

An “immediate release formulation” refers to a formulation that releasesgreater than or equal to about 80% of the pharmaceutical agent in lessthan or equal to about 30 min.

For the purposes of this application, an enhancing agent (“enhancer”) isdefined as any non-pharmaceutically active ingredient that improves thetherapeutic potential of a formulation.

“Sustained release” is defined herein as release of a pharmaceuticalagent in a continuous manner over a prolonged period of time.

By “prolonged period of time” it is meant a continuous period of time ofgreater than about 1 hour, greater than about 4 hours, greater thanabout 8 hours, greater than about 12 hours, greater than about 16 hours,or up to more than about 24 hours.

As used herein, unless otherwise noted, “rate of release” or “releaserate” or “dissolution rate” of a drug refers to the quantity of drugreleased from a dosage form per unit time, e.g., milligrams of drugreleased per hour (mg/hr) or a percentage of a total drug dose releasedper hour. Drug release rates for dosage forms are typically measured asan in vitro rate of drug release, i.e., a quantity of drug released fromthe dosage form per unit time measured under appropriate conditions andin a suitable fluid. The release rates referred to herein are determinedby placing a dosage form to be tested in a medium in an appropriatedissolution bath. Aliquots of the medium, collected at pre-setintervals, are then injected into a chromatographic system fitted withan appropriate detector to quantify the amounts of drug released duringthe testing intervals.

Side effect is defined herein as a secondary and usually adverse effectof a drug.

Terms such as “treating” or “treatment” or “to treat” or “alleviating”or “to alleviate” refer to both 1) therapeutic measures that cure, slowdown, lessen symptoms of, reverse, and/or halt progression of adiagnosed pathologic condition or disorder and 2) prophylactic orpreventative measures that prevent and/or slow the development of atargeted pathologic condition or disorder. Thus those in need oftreatment include those already with the disorder; those prone to havethe disorder; and those in whom the disorder is to be prevented.Beneficial or desired clinical results include, but are not limited to,alleviation of symptoms, diminishment of extent of disease, stabilized(i.e., not worsening) state of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state, andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment. Those in need oftreatment include those already with the condition or disorder as wellas those prone to have the condition or disorder or those in which thecondition or disorder is to be prevented.

By “subject” or “individual” or “animal” or “patient” or “mammal,” ismeant any subject, particularly a mammalian subject, for whom diagnosis,prognosis, or therapy is desired. Mammalian subjects include humans,domestic animals, farm animals, and zoo, sports, or pet animals such asdogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows,bears, and so on. The meaning of the terms “eukaryote”, “animal”,“mammal”, etc. is well known in the art and can, for example, be deducedfrom Wehner and Gehring (1995; Thieme Verlag). In the context of thisinvention, it is also envisaged that animals are to be treated which areeconomically, agronomically or scientifically important. Scientificallyimportant organisms include, but are not limited to, mice, rats, andrabbits. Non-limiting examples of agronomically important animals aresheep, cattle and pigs, while, for example, cats and dogs may beconsidered as economically important animals. In one embodiment, thesubject/patient is a mammal; in another embodiment, the subject/patientis a human or a non-human mammal (such as, e.g., a guinea pig, ahamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, anape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, agibbon, a sheep, cattle, or a pig); most preferably, the subject/patientis a human.

II. Colchicine

In the following, colchicine used according to the present inventionwill be described in detail. The chemical structure of colchicine(ChemID 2012) is as follows:

The chemical name of colchicine is:N[5,6,7,9-tetrahydro-1,2,3,10-tetratmethoxy9-oxobenzo[a]heptalen-7-yl],(S)-acetamide; molecular formula: C₂₂H₂₅NO₆;CAS number: 64-86-8.

Colchicine is an anti-inflammatory drug with a long history in humanmedicine, used for the symptomatic treatment of inflammatory diseases,most prominently gout. It is a natural product which can be extractedfrom two plants of the lily family, Colchicum autumnale and Gloriosasuperba. Colchicine is a tricyclic alkaloid and has a molecular mass of399.437. The active ingredient colchicine as well as its tabletformulation is listed in various national and internationalpharmacopeias such as the United States Pharmacopeia (USP).

The positive effect of its plant source in the treatment of rheumatismand swelling was described first already around 1500 B.C. in Egypt. Itsuse in gout was first described around 1500 years ago (Graham andRoberts, 1953, Ann Rheum Dis 12(1): 16-9). Today, the therapeutic valueof colchicine is well established in a number of inflammatory diseasesand approved by FDA for the prophylaxis and treatment of acute goutflares and familial Mediterranean fever (FMF). Other importantestablished, though off-label uses are amongst others, Behçet's diseaseand recurrent pericarditis. In all known indications, it is generallyadministered orally as solid tablets in strengths of 0.5-0.6 mg/tablet(e.g. Europe and United States, respectively). The pharmacotherapeuticmechanism of action of colchicine in diverse disorders is not fullyunderstood, though it is known that the drug accumulates preferentiallyin leucocytes, particularly neutrophils which is important for itstherapeutic effect. Three major interactions of colchicine with specificproteins modulate its pharmacokinetics: tubulin, cytochrome P450 3A4(CYP3A4), and P-glycoprotein. It is assumed that most therapeuticeffects of the drug are related to its capacity to bind to β-tubulin,thus inhibiting self-assembly and polymerization of microtubules.Availability of tubulin is essential for several cellular functions suchas mitosis. Therefore colchicine effectively functions as a “mitoticpoison” or spindle poison. By inhibiting microtubule self-assembly,colchicine interferes with many cellular functions involved in theimmune response such as modulation of the production of chemokineschemokines and prostanoids and inhibition of neutrophil and endothelialcell adhesion molecules. Eventually it decreases neutrophildegranulation, chemotaxis and phagocytosis, thus reducing the initiationand amplification of inflammation. Colchicine also inhibits uric acidcrystal deposition (a process important to the genesis of gout), whichis enhanced by a low pH in the tissues, probably by inhibiting oxidationof glucose and subsequent lactic acid reduction in leukocytes (Imazio,Brucato et al. 2009, Eur Heart J, 30(5): 532-9; Cocco, Chu et al. 2010,Eur J Intern Med, 21(6): 503-8; Stanton, Gernert et al. 2011, Med ResRev, 31(3): 443-81). In the management of pericarditis, colchicineexcerpts its therapeutic effect by suppressing the acute pericardialinflammation. However, the exact cellular and molecular mechanisms ofhow colchicine relieves pain and inflammation in acute pericarditis andprevents recurrences are not fully understood.

Colchicine in the context of the present invention can be used for theprevention and/or treatment of cardiovascular diseases and/orinflammatory diseases.

III. Treatment Methods Using Colchicine Concurrently with anAntithrombotic Agent

The present invention also presents a method of treatment or preventionof cardiovascular diseases, cardiovascular events and/or inflammatorydisorders in a subject, comprising administering to the subject atherapeutically effective amount of colchicine of the present invention,wherein colchicine is administered concurrently with at least oneantithrombotic agent. There are three classes of antithrombotic drugs,including anticoagulants, antiplatelet agents, and thrombolytic agents.As used herein, the term “anticoagulants” refers to drugs that slow downclotting, thereby reducing fibrin formation and preventing clots fromforming and growing. Examples of anticoagulants include, but are notlimited to, novel oral anticoagulants (NOACs) (including dabigatran,rivaroxaban, and apixaban), coumarins (vitamin K antagonists) (includingwarfarin (Coumadin), acenocoumarol and phenprocoumon, atromentin,brodifacoum, phenindione), heparin and derivatives, low molecular weightheparin (including dalteparin and enoxaparin), synthetic pentasaccharideinhibitors of factor Xa, direct factor Xa inhibitors (includingrivaroxaban, apixaban, edoxaban, and darexaban), direct thrombininhibitors (including hirudin, lepirudin, bivalirudin, ximelagatrain),and antithrombin protein therapeutics. As used herein, the term“antiplatelet agent” refers to drugs that prevent platelets fromclumping and also prevent clots from forming and growing. Examples ofantiplatelet agents include, but are not limited to, irreversiblecyclooxygenase inhibitors (including aspirin and triflusal), adenosinediphosphate (ADP) receptor inhibitors (including clopidogrel, prasugrel,ticagrelor and ticlopidine), phosphodiesterase inhibitors (includingcilostazol), protease-activated receptor-1 (PAR-1) antagonists(including vorapaxar), glycoprotein IIB/IIIA inhibitors (includingabciximab, eptifibatide, tirofiban), adenosine reuptake inhibitors(including dipyridamole), and thromboxane inhibitors (includingthromboxane synthase inhibitors and thromboxane receptor antagonistssuch as terutroban. As used herein, the term “thrombolytic agent” refersto drugs that are able to dissolve a clot (thrombus) and reopen anartery or vein. Thrombolytic agents are used for the treatment ofmyocardial infarction (heart attack), thromboembolic strokes, deep veinthrombosis and pulmonary embolism to clear a blocked artery and avoidpermanent damage to the perfused tissue (e.g. myocardium, brain, leg)and death. Examples of thrombolytic agents include, but are not limitedto, tissue plasminogen activator (t-PA), e.g., alteplase, reteplase,tenecteplase; anistreplase; streptokinase; and urokinase.

In one embodiment, the present invention can be used to treatcardiovascular diseases and/or inflammatory disorders, including, butnot limited to, acute vascular diseases, such as myocardial infarction,stroke, peripheral arterial occlusion, deep vein thrombosis, pulmonaryembolism, and other blood system thrombosis. Such disorders are causedby either partial or total occlusion of a blood vessel by a blood clot,which consists of fibrin and platelet aggregates. Therapeuticintervention with colchicine concurrently with at least one agent thatprevents or delays clot formation (i.e., anticoagulants and antiplateletagents) or with an agent that dissolves blood clots may, in oneembodiment, effectively slow clot formation and enhance clot dissolutionin blood. In another embodiment, administering colchicine concurrentlywith at least one antithrombotic agent may delay clotting time and/ormay change the character of the clot that is formed to a looser, lessstable clot. Accordingly, administering colchicine concurrently with atleast one antithrombotic agent is useful in the treatment ofcardiovascular and/or thrombotic disorders, for dissolving or lysingclots in cardiovascular and/or thrombotic patients, for delaying orinhibiting hard clot formation or supplementing cardiovascular and/orthrombolytic therapy in the patients.

According to the present invention, colchicine as described herein isadministered in the form of a sustained release preparation or in animmediate release formulation. An example of a sustained releaseformulation of colchicine can be found in PCT/IB2014/001201(WO2014/170755), which is hereby incorporated by reference in itsentirety. An example of an immediate release formulation is anycommercially available immediate release formulation of colchicine.

“Concurrent administration,” or “co-administration” or “co-treatment,”as used herein includes administration of the agents, in conjunction orcombination, together, or before or after each other. It can also referto administering the agents in a fixed combination such as in a singledosage form (i.e., one pill or tablet). In one embodiment of the presentinvention, colchicine can be administered with at least oneantithrombotic agent in a single dosage form. Providing the therapeuticagents in a single dosage form (i.e., one pill or tablet) has the effectof reducing the number of medications that a patient takes in one day,which can improve patient adherence to the treatment regimen.

Conventional antithrombotic agents are expected to be administered indosages and by routes consistent with the usual clinical practice. Thetypical dosages and administration regimens for some of theseantiplatelet, anticoagulant and thrombolytic agents, when administeredas monotherapy, are discussed below. Naturally, these dosages may varyas determined by good medical practice and the clinical condition of theindividual patient. The daily dosage amount of aspirin may vary frompatient to patient. Some patients, for example, may only require verylow doses of aspirin, such as 75 mg daily, which is less than a standardinfant aspirin dose. Other patients may receive a daily dosage amountfrom 81 mg, the amount in an infant aspirin, to 325 mg, the amount in aregular strength tablet. The daily dosage amount of warfarin must beindividualized according to the patient's sensitivity to the drug asindicated by its effect on the prothrombin time (PT) ratio. The loadingdose is typically 2 to 5 mg/day and most patients are satisfactorilymaintained at a dose of 2 to 10 mg/day. Warfarin is generally givenorally but may be administered intravenously if the patient cannot takethe drug orally. The daily dosage amount of clopidogrel must also beindividualized according to the patient's sensitivity to the drug aswell as to any other medications the patient is taking. The loading doseis typically 300 mg/day and the daily dose is generally between 75 mgand 100 mg.

When colchicine is concurrently administered with at least oneantithrombotic agent, the colchicine and the antithrombotic agent mayeach be administered in amounts that would be sufficient formonotherapeutic effectiveness, or they may be administered in amountless than what would be sufficient for monotherapeutic amounts, referredto herein as the “adjusted daily dosage amount”. In one embodiment,colchicine may be capable of improving the therapeutic effectiveness ofexisting anticoagulant or thrombolytic agents, which would reduce thedosages of colchicine and/or the antithrombotic agent needed to exerttheir desired anticoagulant or thrombolytic effects. This reduction ofdosage amount would, in turn, decrease the risk of adverse side effectsassociated with the use of thrombolytic agents, including, for example,undesirable internal or external bleeding. The use of colchicine mayfurther improve the therapeutic effectiveness of the otherantithrombotic agents in a variety of ways. For example, lowering thedosage of the antithrombotic agent required for therapeuticeffectiveness reduces toxicity and/or cost of treatment, and thus allowswider use of the agent. Alternatively, concurrent administration mayproduce an increased, more rapid or more complete anticoagulant orthrombolytic effect than could be achieved with either agent alone.

In accordance with one embodiment of the present invention, whencolchicine is concurrently administered with at least one antithromboticagent, the daily dosage amount of colchicine may be between 25% and 75%of the daily dosage amount of colchicine when colchicine is administeredin the absence of at least one antithrombotic agent. In one embodiment,if the daily dosage amount of colchicine is 0.6 mg, then the adjusteddosage daily amount of colchicine used concurrently with at least oneantithrombotic agent may be between about 0.15 mg to about 0.45 mg. Inanother embodiment, if the daily dosage amount of colchicine is 0.55 mg,then the adjusted dosage daily amount of colchicine used concurrentlywith at least one antithrombotic agent may be between about 0.13 mg toabout 0.43 mg. In one embodiment, if the daily dosage amount ofcolchicine is 0.5 mg, then the adjusted dosage daily amount ofcolchicine used concurrently with at least one antithrombotic agent maybe between about 0.10 mg to about 0.40 mg.

In accordance with another embodiment of the present invention, whencolchicine is concurrently administered with at least one antithromboticagent, the daily dosage amount of the antithrombotic agent may bebetween 25% and 75% of the daily dosage amount of the antithromboticagent when the antithrombotic agent is administered in the absence ofcolchicine.

In one embodiment, treatment includes the application or administrationof a colchicine formulation as described herein to a patient, where thepatient has, or has the risk of developing a cardiovascular diseaseand/or an inflammatory disorder. In another embodiment, treatment isalso intended to include the application or administration of apharmaceutical composition comprising the colchicine formulation, to apatient, where the patient has, or has the risk of developing acardiovascular disease and/or inflammatory disorder.

As used herein, the term “cardiovascular disease” refers to any diseaseinvolving the heart and/or the vascular system (all blood vessels incl.arteries, capillaries and veins). This includes all diseases listed inchapter IX “Diseases of the circulatory system (I00-I99)” of theInternational Statistical Classification of Diseases and Related HealthProblems 10th Revision (ICD-10) Version for 2010, by the World HealthOrganisation.

More specifically, all diseases of this ICD-10 class which involve a)inflammation of any part of the heart or blood vessel as well as b)ischemia/atherosclerosis/thickening of any blood vessel of thecirculatory system.

Colchicine as described herein is for use in the treatment and/orprevention of any inflammatory disorder involving the heart tissueselected from ICD-10 sections 100-199. More specifically, these includeacute and recurrent pericarditis as well as post-surgical complicationsinvolving inflammation of the pericardium (Postcardiotomy syndrome,Postpericardiotomy syndrome, pericardial effusion). Other inflammatoryheart diseases covered are any form of myocarditis, endocarditis andarterial fibrillation.

The proposed mechanism of action in this indication is the inhibition ofplaque instability by neutrophil inhibition. In stable coronary disease,fatty materials accumulate at the blood vessel and form a stable plaque.This plaque may become subject to attack by neutrophils. This may causeplaque instability and consequently leads to plaque rupture and clinicalevents. Therefore, colchicine as described herein is for use intreatment and/or prevention of any disease of the cardiovascular systemwhich involves ischemia, atherosclerosis and/or thickening of bloodvessels (arteries, capillaries, veins) due to plaque formation with arisk of clinical events due to plaque instability. Claimed are alldiseases classified in ICD-10 section 100-199 fulfilling any of theserequirements. Examples are stable coronary disease, cardiovascularatherosclerosis, and atherosclerosis of the peripheral vascular system,Abdominal Aortic Aneurysm (AAA) and carotid and iliofemoral/renalatheromas (e.g. I25, I70).

In the context of the present invention, an acute cardiovascular eventin a patient with stable cardiovascular disease is preferably acardiovascular event in a patient with stable coronary disease. In thecontext of the present invention, the term “stable coronary disease” and“stable coronary heart disease” have the same meaning and are usedinterchangeable. Both terms include the medical condition stablecoronary artery disease (SCAD). “Stable” in the context of the terms“stable cardiovascular disease”, “stable coronary disease” or “stablecoronary heart disease” is defined as any conditions of diagnosedcardiovascular disease in the absence of acute cardiovascular events.Hence, e.g. stable coronary disease defines the different evolutionaryphases of coronary disease, excluding the situations in, which coronaryartery thrombosis dominates clinical presentation (acute coronarysyndrome).

Colchicine in the context of the present invention can be used for theprevention and/or treatment of cardiovascular diseases and/orcardiovascular events. Cardiovascular diseases include, but are notlimited to, heart diseases as described, e.g., in Robbins and Cotran,Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier.Cardiovascular disease refers to a group of diseases of the circulatorysystem including the heart, blood and lymphatic vessels. In particular,cardiovascular disease may include vascular diseases involvingatherosclerosis, plaque formation or disposition. The most commoncardiovascular diseases are coronary heart disease and stroke.Non-limiting examples of cardiovascular disease which may be preventedor treated according to the methods of the invention include coronaryheart disease (disease of the blood vessels supplying the heart muscle),cerebrovascular disease (disease of the blood vessels supplying thebrain), peripheral arterial disease (disease of blood vessels supplyingthe arms and legs), rheumatic heart disease (damage to the heart muscleand heart valves from rheumatic fever, caused by streptococcalbacteria), congenital heart disease (malformations of heart structureexisting at birth), deep vein thrombosis and pulmonary embolism (bloodclots in the leg veins, which can dislodge and move to the heart andlungs), hyperlipemia (an excessive level of blood fats, such as LDL),high blood pressure, coronary artery disease, atherosclerosis, ischemicdiseases, abdominal aortic aneurism, carotid and iliofemoral/renalatheromas, heart failure, cardiac rhythm defects, arteriosclerosis,heart attack and stroke. Heart attacks and strokes are usually acuteevents and are mainly caused by a blockage that prevents blood fromflowing to the heart or brain. The most common reason for this is abuild-up of fatty deposits on the inner walls of the blood vessels thatsupply the heart or brain. Strokes can also be caused by bleeding from ablood vessel in the brain or from blood clots.

Especially, in the context of the present invention, colchicineconcurrently with at least one antithrombotic agent can be used for theprevention of acute pericarditis, recurrent pericarditis, recurrentpericarditis in patients with a history of pericarditis,post-pericardiotomy syndrome (PPS), PPS in patients undergoing cardiacsurgery, and cardiovascular events in patients with stable coronary(heart) disease (the cardiovascular events can be acute cardiovascularevents).

Pericarditis is an inflammatory disease involving the pericardium, athin double-walled fibroelastic sac, surrounding the heart. Due toinflammation, it comes to irritation and swelling of the pericardium.This causes the sac to rub against the heart which causes chest pain,the most common symptom of pericarditis. Pericarditis is the most commonform if inflammatory disorder of the heart, though very rare on apopulation basis. Pericarditis is very heterogeneous in its origin,clinical manifestations and duration of symptoms. It can either occur asisolated clinical problem or as a manifestation of a systemic disease.In most cases (90%), pericarditis is of idiopathic (spontaneous,unknown) etiology but may also occur secondary to systemic infections,acute myocardial infarction or autoimmune diseases. Thepost-pericardiotomy syndrome (PPS) may be a troublesome complicationfollowing cardiac surgery occurring a few days to several weeks afterthe surgical operation. The estimated incidence of the syndrome has arelatively wide range affecting from 10 to 40% of patients submitted tocardiac surgery (Prince and Cunhe, 1997, Heart Lung, 26:165).

Non-limiting examples of (acute) cardiovascular events are injury of theatherosclerotic wall, acute coronary syndrome, out-of-hospital cardiacarrest, or non-cardioembolic ischemic stroke. Further such events aredescribed, e.g., in Robbins and Cotran, Pathologic Basis of Disease,Eighth Edition, Saunders Elsevier. In some contexts, the cardiovascularevent is not acute pericarditis. In some contexts, the cardiovascularevent is not recurrent pericarditis.

In an embodiment, the use of colchicine concurrently with at least oneantithrombotic agent may be used to treat inflammatory disease otherthan those mentioned above. In an embodiment, the inflammatory diseaseincludes, but is not limited to, gout, familial Mediterranean fever,Behcet's disease, Age-related macular degeneration and Alzheimer'sdisease.

Patients/subjects which suffer from the above described disease and/orwhich are suitable for treatment with colchicine according to thepresent invention can be diagnosed by conventional and/or routineprocedures. The skilled person is well aware of them. Diagnosis is alsodescribed, e.g., in Robbins and Cotran, Pathologic Basis of Disease,Eighth Edition, Saunders Elsevier.

In an embodiment, the use of colchicine concurrently with at least oneantithrombotic agent as described herein is useful for the treatment ofvarious cardiovascular diseases, cardiovascular events and/orinflammatory disorders. In some embodiments, treatment of acardiovascular disease, cardiovascular event and/or an inflammatorydisorder is intended to include remediation of, improvement of,amelioration of, lessening of the severity of, or reduction in the timecourse of, a disease, disorder or condition, or any parameter or symptomthereof. In an embodiment of the present invention, the term “disorder”,“disease”, or “condition” is to be understood as cardiovascular diseaseand/or inflammatory disorder as described above. In the context of thepresent invention, “amelioration” refers, without limitation, to anyobservable beneficial effect.

In accordance with the present invention, the colchicine formulationherein can be used to promote a positive therapeutic response withrespect to the cardiovascular disease and/or inflammatory disorder. A“positive therapeutic response” with respect to the cardiovasculardisease and/or inflammatory disorder is intended to include animprovement in the disease can be evidenced by, for example, a delayedonset of clinical symptoms of the disease or condition, a reduction inseverity of some or all clinical symptoms of the disease or condition, aslower progression of the disease or condition, an improvement in theoverall health or well-being of the subject, or by other parameters wellknown in the art that are specific to the particular disease.

In another embodiment, the use of colchicine concurrently with at leastone antithrombotic agent as described herein is useful in the preventionof various cardiovascular diseases, cardiovascular events and/orinflammatory disorders. In the context of the present invention, theterm “prevention” is well known in the art. For example, apatient/subject suspected of being prone to suffer from a disorder ordisease as defined herein may, in particular, benefit from a preventionof the disorder or disease. The subject/patient may have asusceptibility or predisposition for a disorder or disease, includingbut not limited to hereditary predisposition. Such a predisposition canbe determined by standard assays, using, for example, genetic markers orphenotypic indicators. It is to be understood that a disorder or diseaseto be prevented in accordance with the present invention has not beendiagnosed or cannot be diagnosed in the patient/subject (for example,the patient/subject does not show any clinical or pathologicalsymptoms). Thus, the term “prevention” comprises the use of compounds ofthe present invention before any clinical and/or pathological symptomsare diagnosed or determined or can be diagnosed or determined by theattending physician. Prevention includes, without limitation, to avoidthe disease or condition from occurring in patient and/or subject thatmay be predisposed to the disease but does not yet experience or exhibitsymptoms of the disease (prophylactic treatment).

The use of colchicine concurrently with at least one antithromboticagent according to the present invention may also be used concurrentlywith other conventional therapies for any of the diseases disclosedherein. Such conventional therapies are well known in the art and theskilled person knows any such therapies. Colchicine concurrently with atleast one antithrombotic agent as described herein may also be usedconcurrently with colchicine-compatible statins. In general,non-limiting examples of statins are atorvastatin (Lipitor®, Torvast®),fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®),pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®, Selektine®,Lipostat®), rosuvastatin (Crestor®) and simvastatin (Zocor®, Lipex®). Inconnection with the present invention, colchicine-compatible statins areused. Preferably, in the context of the present invention, thecombination of the composition of the present invention with thecolchicine-compatible statins are accomplished in connection with stablecoronary heart disease. Such statins preferably are statins which, dueto the nature of their mechanism of action, metabolism and/or clearancedo not, or only to a small extent, interfere with the mechanism ofaction, metabolism and/or clearance of colchicine and therefore show areduced risk, severity and/or incidence of drug-related drug adverseevents when given concurrently with colchicine.

In an embodiment, the use of colchicine is in fixed (within the samepharmaceutical preparation) or unfixed (different pharmaceuticalpreparation) combination. “Fixed combination” is to be understood asmeaning a combination whose active ingredients are combined at fixeddoses in the same vehicle (single formula) that delivers them togetherto the point of application. Fixed combination can mean, e.g., in asingle tablet, solution, cream, capsule, gel, ointment, salve, patch,suppository or transdermal delivery system. “Unfixed combination” asused herein is to be understood as meaning that the activeingredients/components are in more than one vehicle (e.g. tablets,solutions, creams, capsules, gels, ointments, salves, patches,suppositories or transdermal delivery systems). Each of the vehicles cancontain a desired pharmaceutical composition or active component. Forexample, a preferred unfixed combination as described herein means thatone vehicle contains colchicine, as described herein, and anothervehicle contains a colchicine-compatible statin, as described herein.Examples of colchicine as described herein in fixed or unfixedcombination(s) encompass(es) colchicine concurrently with one or morecolchicine-compatible statins selected from the group consisting ofatorvastatin, rosuvastatin, simvastatin and pravastatin. Specifically,colchicine as described herein in fixed or unfixed combination is to beunderstood as meaning colchicine concurrently with atorvastatin.Specifically, colchicine as described herein in fixed or unfixedcombination is to be understood as meaning colchicine concurrently withrosuvastatin. Specifically, colchicine as described herein in fixed orunfixed combination is to be understood as meaning colchicineconcurrently with simvastatin. Specifically, colchicine as describedherein in fixed or unfixed combination is to be understood as meaningcolchicine concurrently with pravastatin.

In some embodiments, the use of colchicine concurrently with at leastone antithrombotic agent as described herein may be used concurrentlywith a statin and another agent, such as ezetimibe/simvastatin.Colchicine as described herein may be used concurrently with otherdrugs, e.g, which are used in medicine and are known to the skilledperson (e.g. antibiotics, NSAID (non-steroidal anti-inflammatory drugs),corticosteroids).

VI. Administration Methods

Methods of preparing and administering colchicine of the presentinvention to a subject in need thereof are well known to or are readilydetermined by those skilled in the art. The route of administration ofthe colchicine formulation can be, for example, oral, parenteral, byinhalation or topical. The term parenteral as used herein includes,e.g., intravenous, intraarterial, intraperitoneal, intramuscular,subcutaneous, rectal, or vaginal administration.

Colchicine when used as a composition in the context of the presentinvention may include one or more pharmaceutically acceptable carriersand thus may be prepared in the form of a local formulation, in orderfor it to be administered. The pharmaceutically acceptable carrier mayinclude saline, sterile water, linger liquid, buffer saline, a dextrosesolution, a malto dextrin solution, glycerol, ethanol and mixtures ofone or more thereof, and also may include an additive such as anantioxidant, a buffer, a bacteriostatic agent or the like, as necessary.Furthermore, a diluent, a dispersant, a surfactant, a binder and alubricant may be added when the composition according to the presentinvention is prepared, e.g., in the form of a local formulation such asan ointment, lotion, cream, gel, skin emulsion, skin suspension, patchor spray.

Non-limiting examples for administration of the compound and orcompositions according to the present invention include coated anduncoated tablets, soft gelatine capsules, hard gelatine capsules,lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs,powders and granules for reconstitution, dispersible powders andgranules, medicated gums, chewing tablets and effervescent tablets. Thecomposition according to the present invention can administered in anypharmaceutical form for oral (e.g. solid, semi-solid, liquid), dermal(e.g. dermal patch), sublingual, parenteral (e.g. injection), ophthalmic(e.g. eye drops, gel or ointment) or rectal (e.g. suppository)administration. In an embodiment, the composition is formulated as atablet, capsule, suppository, dermal patch or sublingual formulation.

The pharmaceutical compositions used in this invention comprisepharmaceutically acceptable carriers, including, e.g., ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol, andwool fat.

Certain pharmaceutical compositions used in this invention can be orallyadministered in an acceptable dosage form including, e.g., capsules,tablets, aqueous suspensions or solutions. Certain pharmaceuticalcompositions also can be administered by nasal aerosol or inhalation.Such compositions can be prepared as solutions in saline, employingbenzyl alcohol or other suitable preservatives, absorption promoters toenhance bioavailability, and/or other conventional solubilizing ordispersing agents.

The amount of the colchicine formulation to be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. The compositioncan be administered as a single dose, multiple doses or over anestablished period of time in an infusion. Dosage regimens also can beadjusted to provide the optimum desired response (e.g., a therapeutic orprophylactic response).

In some situations, the composition of the present invention can beparenterally administered. Preparations for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, andemulsions. Examples of non-aqueous solvents are propylene glycol,polyethylene glycol, vegetable oils such as olive oil, and injectableorganic esters such as ethyl oleate. Aqueous carriers include, e.g.,water, alcoholic/aqueous solutions, emulsions or suspensions, includingsaline and buffered media. In the subject invention, pharmaceuticallyacceptable carriers include, but are not limited to, 0.01-0.1 M andpreferably 0.05 M phosphate buffer or 0.8% saline. Other commonparenteral vehicles include sodium phosphate solutions, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's, or fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers, such as those based on Ringer's dextrose, andthe like. Preservatives and other additives may also be present such as,for example, antimicrobials, antioxidants, chelating agents, and inertgases and the like.

Parenteral formulations can be a single bolus dose, an infusion or aloading bolus dose followed with a maintenance dose. These compositionscan be administered at specific fixed or variable intervals, e.g., oncea day, or on an “as needed” basis.

The composition according to the present invention may be administeredin a dose range varying depending on the patient's body weight, age,gender, health condition, diet, administration time, administrationmethod, excretion rate and disease severity. The compounds of thepresent invention as compounds per se in their use as pharmacophores oras pharmaceutical compositions can be administered to the patient and/orsubject at a suitable dose. The dosage regiment will be determined bythe attending physician and clinical factors. As is well known in themedical arts, dosages for any one patient depends upon many factors,including the patient's size, body surface area, age, the particularcompound to be administered, sex, time and route of administration,general health, and other drugs being administered concurrently.Generally, the regimen as a regular administration of the pharmaceuticalcomposition comprising the herein defined should be, e.g., in a range asdescribed below. Progress can be monitored by periodic assessment.

The composition according to the present invention can be administeredwith a single dose or with 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses, ifdesired. The composition can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 times per day. Preferably, colchicine according to the presentinvention is administered once per day. More preferably, colchicineaccording to the present invention is administered once per day as asingle dose.

The composition according to the present invention can be administeredregularly for long periods of time. In an embodiment, the compositioncan be administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or moreyears. In another embodiment, the composition can be administeredregularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. Inother embodiments, the composition can be administered regularly for 1,2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks. As used herein, the term“regularly” refers to administration of the composition at regular timesor intervals over a period of time. For instance, the composition may beadministered to a patient once daily for three years. In otherembodiments, the composition may be administered to a patient once everyother day for 5 years. It should be appreciated that the frequency ofadministration may vary based on a number of factors, including, but notlimited to, the severity of disease, the overall health of the patient,any additional medications the patient is taking, and whether thetreatment is prophylactic or not. It should also be appreciated that thefrequency of administration may be adjusted at any point.

The amount/concentration/dose of the composition according to thepresent invention can be between 0.1 mg and 5.0 mg, 0.1 mg and 2.0 mg,0.1 mg to 1.5 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.5 mg,0.25 mg to 5.0 mg, 0.25 mg to 2.0 mg, 0.25 mg to 1.5 mg, 0.25 mg to 1.0mg, 0.25 mg to 0.75 mg or 0.25 mg to 0.5 mg. In an embodiment, thecomposition according to the present invention is administered at adaily dose of colchicine of between about 0.1 mg and about 0.75 mg orbetween about 0.1 mg and about 0.5 mg. In another embodiment, thecomposition according to the present invention is administered at adaily dose of colchicine of between about 0.25 mg to about 0.75 mg orbetween about 0.25 mg to about 0.5 mg. In an embodiment, the compositionaccording to the present invention is administered at a daily dose ofabout 0.5 mg colchicine.

In a preferred embodiment, the amount/concentration of colchicine asused herein can be administered at the first day of administration in ahigher dose (concentration/amount) compared to the administration ofcolchicine at the following days(s) of administration (maintenanceadministration/maintenance dose of administration). Alternatively suchdecreased dose (maintenance dose) can be started after 2, 3, 4, 5, 6, 7,8, 9 or 10 days of initial administration of the higher dose. In casethe course of treatment is any such as described above, the higherdose/amount/concentration of colchicine (e.g. at the first day ofadministration) can be any as described above, provided that themaintenance dose (the dose/amount/concentration of colchicine at thedays following the higher dose/amount/concentration) is lower than theinitial dose/amount/concentration of colchicine (e.g. at the first dayof administration). Preferably, the composition of the invention isadministered with a dose of colchicine of between about 1.0 mg to about2.0 mg at the first day (preferably as a single dose) of administrationand the maintenance dose of colchicine at the following day(s) ofadministration is between about 0.5 mg to about 1.0 mg.

In keeping with the scope of the present disclosure, the colchicineformulation of the present invention can be administered to a human orother animal in accordance with the aforementioned methods of treatmentin an amount sufficient to produce a therapeutic effect. The colchicineformulation can be administered to such human or other animal in aconventional dosage form prepared by combining the colchicineformulation of the invention with a conventional pharmaceuticallyacceptable carrier or diluent according to known techniques. It will berecognized by one of skill in the art that the form and character of thepharmaceutically acceptable carrier or diluent is dictated by the amountof active ingredient with which it is to be combined, the route ofadministration and other well-known variables.

By “therapeutically effective dose or amount” or “effective amount” isintended an amount of the colchicine formulation that when administeredbrings about a positive therapeutic response with respect to treatmentof a patient with a disease to be treated, e.g., an improvement in thedisease can be evidenced by, for example, a delayed onset of clinicalsymptoms of the disease or condition, a reduction in severity of some orall clinical symptoms of the disease or condition, a slower progressionof the disease or condition, an improvement in the overall health orwell-being of the subject, or by other parameters well known in the artthat are specific to the particular disease. In an embodiment, atherapeutically effective dose amount of the composition according tothe present invention can be between 0.1 mg and 5.0 mg, 0.1 mg and 2.0mg, 0.1 mg to 1.5 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.5mg, 0.25 mg to 5.0 mg, 0.25 mg to 2.0 mg, 0.25 mg to 1.5 mg, 0.25 mg to1.0 mg, 0.25 mg to 0.75 mg or 0.25 mg to 0.5 mg. In an embodiment, thetherapeutically effective dose amount of the composition according tothe present invention is administered at a daily dose of colchicine ofbetween about 0.1 mg and about 0.75 mg or between about 0.1 mg and about0.5 mg. In another embodiment, the therapeutically effective dose amountof the composition according to the present invention is administered ata daily dose of colchicine of between about 0.25 mg to about 0.75 mg orbetween about 0.25 mg to about 0.5 mg. In an embodiment, thetherapeutically effective dose amount of the composition according tothe present invention is administered at a daily dose of about 0.5 mgcolchicine.

The invention also provides for the use of the colchicine formulation inthe manufacture of a medicament for treating a subject for treating acardiovascular disease, cardiovascular event and/or inflammatorydisorder, wherein the medicament is used in a subject that has beenpretreated or is concurrently being treated with at least one othertherapy. By “pretreated” or “pretreatment” is intended the subject hasreceived one or more other therapies prior to receiving the medicamentcomprising the colchicine formulation. “Pretreated” or “pretreatment”includes subjects that have been treated with at least one other therapywithin 2 years, within 18 months, within 1 year, within 6 months, within2 months, within 6 weeks, within 1 month, within 4 weeks, within 3weeks, within 2 weeks, within 1 week, within 6 days, within 5 days,within 4 days, within 3 days, within 2 days, or even within 1 day priorto initiation of treatment with the medicament comprising the colchicineformulation. By “concurrent” or “concomitant” is intended the subject isreceiving one or more other therapies while at the same time receivingthe medicament comprising the colchicine formulation. It is notnecessary that the subject was a responder to pretreatment with theprior therapy or therapies or a responder to the concurrent therapy ortherapies. Thus, the subject that receives the medicament comprising thecolchicine formulation could have responded, or could have failed torespond, to pretreatment with the prior therapy, or to one or more ofthe prior therapies where pretreatment comprised multiple therapies.

All of the references cited above, as well as all references citedherein, are incorporated herein by reference in their entireties.

While the invention has been illustrated and described in detail inabove, such illustration and description are to be consideredillustrative or exemplary and not restrictive. It will be understoodthat changes and modifications may be made by those of ordinary skillwithin the scope and spirit of the following claims. In particular, thepresent invention covers further embodiments with any combination offeatures from different embodiments described above and below.

The present invention is additionally described by way of the followingillustrative non-limiting examples that provide a better understandingof the present invention and of its many advantages. The followingexamples are included to demonstrate preferred embodiments of theinvention. It should be appreciated by those of skill in the art thatthe techniques disclosed in the examples which follow representtechniques used in the present invention to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLES Example 1: Therapeutic Effects of an Immediate ReleaseFormulation in Patients with Cardiovascular Disease

To assess the therapeutic effects of an immediate release formulation inpatients with cardiovascular disease, a prospective randomized observerblinded end-point trial was conducted to determine whether adding 0.5mg/day of colchicine to standard secondary prevention therapiesincluding aspirin and high dose statins reduces the risk ofcardiovascular events in patients with objectively diagnosed andclinically stable coronary disease. This study is described inPCT/AU2013/001261 and is hereby incorporated in its entirety byreference.

Study Conduct and Design:

The LoDoCo Trial was conducted under the auspices of the Heart ResearchInstitute of Western Australia. It was designed by the principalinvestigators, registered with the Australian Clinical Trial Registry(12610000293066), and received ethics approval from the Human ResearchEthics Committee at Sir Charles Gairdner Hospital Perth WesternAustralia in July 2008. There was no external funding source.

The study had a prospective randomized, open, blinded end-point design.Eligible consenting patients with established coronary diseasepresenting for routine clinical review were randomized to receivecolchicine 0.5 mg/day or no colchicine without any other change to theirmedical therapy. All outcomes were evaluated by an experiencedadjudicator blinded to the treatment allocation.

Study Size and Eligibility:

It was planned to recruit a study population that would include 500patients planned (532 patients randomized as 32 dropped out early), 250randomized to the control group and 250 patients randomized to treatmentwho were tolerant of colchicine for at least 4 weeks after the date oftheir randomization. Patients were eligible for inclusion if they meteach of the following criteria: 1) angiographically proven coronarydisease; 2) aged 35 to 85 years; 3) clinically stable for at least 6months, 4) no major competing co-morbidities or contra-indication tocolchicine therapy, 5) considered to be compliant with therapy andattending routine cardiology follow up appointments, and 6) willing tobe consented and randomized into the study. Patients with a history ofbypass surgery were only eligible if they had undergone bypass surgerymore than 10 years before, or had angiographic evidence of graft failureor had undergone stenting since their bypass surgery. All patientssigned informed consent before randomization.

Randomization:

The randomization sequence was computer generated, kept concealed fromthe investigators at all times and was managed by a research assistantwho had no involvement in the evaluation or management of studypatients. Once the assistant received the consent form, the patients'demographic data were entered into the data base and the investigatorsand patients were advised in writing of the treatment group to which thepatient had been assigned. Despite electing to use the lowest dose ofcolchicine available, it was anticipated that a number of patients wouldwithdraw from therapy early after randomization due to gastrointestinalside effects. In order to ensure that the requisite number of patientsin the treatment arm were actually tolerant of treatment, the protocolallowed for the research assistant to assign a newly recruited patientto treatment if a patient discontinued colchicine due to side effects inthe first month. Patients who were intolerant to therapy remained in thestudy, and were followed in the usual manner and included in the primaryintention to treat analysis.

Intervention:

Patients randomized to active treatment were given a prescription forcolchicine 0.5 mg daily by their referring cardiologist. The drug wasdispensed by their usual chemist, and if requested, patients werereimbursed for the cost of these scripts. All other treatments werecontinued as usual.

Follow-Up and Definition of Clinical Outcomes:

Patient compliance with treatment and outcome data were collected atroutine follow up visits and at the time of any unplanned hospitaladmission. An acute coronary syndrome (ACS) was defined as either (a)Acute Myocardial Infarction (AMI), as evidenced by acute ischemic chestpain associated with a rise in serum troponin above the upper limit ofnormal or (b) Unstable Angina (UA), as evidenced by a recentacceleration of the patient's angina unassociated with a rise in serumtroponin but associated with angiographic evidence of a change in thepatient's coronary anatomy. (Unstable Angina Braunwald classificationtypes IB and IIB). The ACS was characterized as being stent-related ifthere was evidence of significant in-stent stenosis or acute stentthrombosis. Out of Hospital Cardiac Arrest was defined as either asudden death as evidenced on the patient's death certificate, or anon-fatal out of hospital cardiac arrest, defined as a recovery fromsudden collapse associated with documented asystole, ventriculartachycardia or ventricular fibrillation. Noncardio-embolic ischemicstroke was defined as CT or MRI proven ischemic stroke adjudged by thetreating neurologist as not being due to atrial fibrillation orintracranial hemorrhage.

The primary efficacy outcome was the present of a cardiovascular eventsuch as ACS, fatal or non-fatal out of hospital cardiac arrest ornon-cardio-embolic ischemic stroke. Secondary outcomes were (a)individual components of the primary outcome, and (b) the components ofACS unrelated to stent disease.

Timelines:

The pre-specified study duration was a minimum follow up of two years inall patients. Accordingly the study was closed on May 31, 2012. DuringMay, all living patients were contacted by phone to collect complianceand outcome data from the last date of follow-up. Final outcome datawere available in all patients and no patients were lost to follow up.

Statistical Power:

Assuming that the control group had a combined cardiovascular event rate(ACS, out of hospital cardiac arrest or non cardio-embolic-ischemicstroke) of 8%, an accrual interval of 2 years and a follow-up after theaccrual interval of 2 years, the planned sample size provided >80% powerto detect a hazard ratio of <0.50 based on a two sided significancelevel of 5%.

Data Analysis:

Summary statistics, including mean and standard deviation werecalculated for all baseline characteristics by treatment arm. All timeto event outcomes were calculated in days by subtracting the date ofrandomization from either: (1) the date of event or death; or (2) thetrial termination date for those patients not experiencing the definedevent. As pre-specified, the primary efficacy analysis was based on theintention-to-treat principle. The intention-to-treat analysis includedall randomized subjects and all events during the time fromrandomization to the trial termination. Trial termination date was fixedas May 31, 2012. A secondary pre-specified on-treatment analysis wasalso performed, based on patients who were both tolerant and compliantto therapy beyond the first month of randomization. All events duringthe time from randomization until non-compliance with colchicinetreatment regimen were included in this analysis.

The time-to-first-event for all outcomes is presented using aKaplan-Meier plot. The primary efficacy outcome was analyzed using a coxproportional hazards model including treatment group coded as control orcolchicine. The secondary outcomes were analysed similarly. In addition,the primary analysis was stratified by gender, age, diagnosis ofdiabetes, past myocardial infarction, unstable angina, coronary bypasssurgery, coronary angioplasty, and therapy with aspirin, clopidogrel orboth, high dose statin therapy (defined as a dose of statin equivalentto atorvastatin of 40 mg or more), beta blockers, calcium blockers andACE inhibitors.

Results:

Between August 2008 and May 2010, 901 patients with stable coronarydisease attending for routine out-patient cardiology review wereassessed for eligibility for the study. Of these, 297 (33%) did not meetthe entry criteria, 72 (8%) declined to participate and 532 (59%) wereenrolled into the study, 250 of whom were randomized to the controlgroup and 282 to treatment. Of those randomized to treatment 32 (11%)reported early intolerance, due to gastrointestinal side effects, and 7patients subsequently reported that they chose not start therapy. All532 randomized patients were followed for the duration of the studyperiod which ranged from a minimum of 24 to a maximum of 44 months.Median follow up was 36 months.

Outcomes:

A primary outcome occurred in 55/532 patients, including 15/282 (5.3%)patients assigned to colchicine treatment, and 40/250 (16%) patientsassigned to the control group [hazard ratio 0.33, 95% CI; 0.18-0.59;p<0.001, number needed to treat 11). A sensitivity analysis wasperformed for the primary outcome, adjusting for the usage of calciumchannel blockers and beta blocker therapy. These results were consistentwith the primary analysis.

The effect of colchicine on the primary outcome was evident early andthe benefits of colchicine continued to accrue throughout the follow upperiod. There was no evidence of differential treatment effects based onany of the clinical or therapeutic variables.

The reduction in the primary outcome was largely driven by the reductionin the number of patients presenting with an ACS, (13/282 (4.6%) vs.34/250 (13.4%), hazard ratio 0.33; 95% CI; 0.18-0.63; p<0.001). Out ofhospital cardiac arrest and non-cardio-embolic ischemic stroke wereinfrequent but were also reduced in the treatment group.

Of the 47 patients who presented with an ACS, the event was stentrelated in 8 (17%) (2 in each group had evidence of acute stentthrombosis and 2 in each group had evidence of significant in-stentstenosis). Further analysis confirmed that patients randomized totreatment were less likely to present with an ACS unrelated to stentdisease (9/282 (3.2%) vs. 30/250 (12%) hazard ratio 0.26, 95% CI;0.12-0.55; p<0.001), be it associated with an AMI (4/282 (1.4%) vs.14/250 (5.6%) hazard ratio 0.25, 95% CI; 0.08-0.76; p=0.014) or UA(5/282 (1.8%) vs. 16/250 (6.4%) hazard ratio 0.27, 95% CI; 0.10-0.75;p=0.011).

Of 39 patients randomized to treatment who did not receive therapybeyond the first month due to early intolerance or non-compliance, 4(10%) presented with an ACS due to acute stent thrombosis (n=1) and UA(n=3). Patients who were both compliant and tolerant to therapy beyondthe first month of randomization had significantly fewer events than thecontrol patients (11/243 (4.5%) vs. 40/250 (16%) hazard ratio 0.29, 95%CI; 0.15-0.56; p<0.001). The results of all on-treatment analyses wereconsistent with those based upon the intention to treat analyses.

Ten patients in the control group died compared with 4 patients in thecolchicine group. Of the 10 controls, 5 died of presumed cardiac cause;2 following an out-of-hospital cardiac arrest, 2 from cardiogenic shockfollowing myocardial infarction, and 1 following bypass surgery. All 4patients in the colchicine group died of non-cardiac causes.

The table below shows primary outcome (i.e., cardiovascular event suchas acute coronary syndrome, out-of-hospital cardiac arrest ornoncardioembolic ischemic stroke) in patients receiving at least oneantithrombotic agent, such as aspirin, clopidogrel or warfarin. Mostpatients also received additional medical such as beta blockers,statins, etc. As seen in the data, a primary outcome was less inpatients receiving colchicine and at least one antithrombotic agent(4.5%) than in patients receiving at least one antithrombotic agent butnot colchicine (16%). Moreover, primary outcome was less in patientsreceiving colchicine and at least aspirin (4.67%) than in patientsreceiving at least aspirin but no colchicine (14.7%). In other words,the addition of colchicine to patients receiving at least oneantithrombotic agent, such as aspirin, further reduces the incidence ofa primary outcome such as acute coronary syndrome, fatal or non-fatalout of hospital cardiac arrest or non-cardio-embolic ischemic stroke.

Colchicine Primary Control Primary group Outcome group Outcome Total*243 11 (4.5%) 250 40 (16%) Treated with at least 242 11 (4.5%) 250 40(16%) one antithrombotic drugs (at least aspirin, clopidogrel orwarfarin or combinations thereof) Treated with a least 226 11 (4.9%) 23637 (15.6%) one antiplatelet drug (at least aspirin, clopidogrel orcombinations thereof) Treated with at least 214 10 (4.67%) 224 33(14.7%) aspirin Treated with Aspirin 173 7 (4%) 197 27 (13.7%) aloneTreated with Aspirin + 33 3 (9%) 25 6 (24%) clopidogrel Treated withAspirin + 6 0 (0%) 2 0 (0%) warfarin Treated with Aspirin + 2 0 (0%)clopidogrel + warfarin Treated with 28 1 (3.45%) 26 7 (26.9%)Clopidogrel alone or warfarin alone (no aspirin) Treated with 12 1(8.3%) 12 4 (33%) Clopidogrel alone Treated with Warfarin 16 0 (0%) 14 3(21.4%) alone No treatment 1 0 (0%) 0 n/a

This trial demonstrates that the addition of colchicine 0.5 mg/day tostandard therapy in patients with stable coronary disease significantlyreduces the risk of a cardiovascular event, including an ACS, out ofhospital cardiac arrest and non-cardio-embolic ischemic stroke. Thebenefits of colchicine were achieved on a background of widespread useof effective secondary prevention strategies, including high dosestatins, as evidenced by the low event rate in the control group. Theeffect of adding colchicine became evident early, continued to accrueover time and was largely driven by a reduction in ACS unrelated tostent disease.

Many modifications and other embodiments of the inventions set forthherein will come to mind to one skilled in the art to which theseinventions pertain having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. Therefore, it is tobe understood that the inventions are not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims and listof embodiments disclosed herein. Although specific terms are employedherein, they are used in a generic and descriptive sense only and notfor purposes of limitation.

What is claimed is:
 1. A method of treating and/or reducing the risk of inflammation in a subject, the method comprising: administering colchicine, a salt thereof, and/or any combination thereof to a subject in need thereof.
 2. The method of claim 1, wherein inflammation is inflammation of any part of the heart or blood vessel.
 3. The method of claim 1, wherein the subject has, or has been diagnosed with, atherosclerotic vascular disease.
 4. The method of claim 3, wherein the atherosclerotic vascular disease is coronary disease.
 5. The method of claim 1, wherein the composition is administered once per day.
 6. The method of claim 1, wherein about 0.5 to about 0.7 mg of colchicine, a salt thereof, and/or any combination thereof is administered to the subject.
 7. The method of claim 1, wherein inflammation is cholesterol crystal induced inflammation within atherosclerotic plaques.
 8. The method of claim 6, wherein about 0.6 mg of colchicine, a salt thereof, and/or any combination thereof is administered to the subject.
 9. The method of claim 1, wherein the composition is administered orally, topically, parenterally, ophthalmically, intraventricularly, intraperitoneally, buccally, rectally, vaginally, intranasally, or by aerosol administration and/or inhalation spray
 10. The method of claim 1, wherein the composition is administered in the form of a tablet, capsule, liquid dose, gel, or powder.
 11. The method of claim 1, wherein the subject receives concurrent treatment with at least one anticoagulant agent or antiplatelet agent.
 12. The method of claim 11, wherein the antiplatelet agent and/or the anticoagulant agent is aspirin.
 13. The method of claim 11, wherein the antiplatelet agent is one or more of an irreversible cyclooxygenase inhibitor, an adenosine diphosphate (ADP) receptor inhibitor, a phosphodiesterase inhibitor, a protease-activated receptor-1 (PAR-1) antagonist, a glycoprotein IIB/IIIA inhibitor, an adenosine reuptake inhibitor, and a thromboxane inhibitor.
 14. The method of claim 1, further comprising co-administering to the subject a therapeutically effective amount of a second agent for the treatment and/or reduction of risk of the cardiovascular event.
 15. The method of claim 14, wherein the second agent is a statin.
 16. The method of claim 15, wherein the statin is atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin, pravastatin, any salt thereof, or any combination thereof.
 17. The method of claim 1, wherein the composition is administered in the form of a tablet, capsule, liquid, powder, or gel.
 18. The method of claim 4, wherein the subject is concurrently administered an agent for the treatment and/or reduction of the risk of an atherosclerotic vascular disease.
 19. The method of claim 18, wherein the agent is a statin.
 20. The method of claim 19, wherein the statin is atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin, pravastatin, a salt thereof, or any combination thereof.
 21. The method of claim 1, wherein the composition of colchicine is administered as an immediate release formulation.
 22. The method of claim 1, wherein the composition is administered approximately daily over a period of at least two years.
 23. A method of treating and/or reducing the risk of atherosclerotic vascular disease in a subject in need thereof, which comprises administering to the subject a composition comprising about 0.5 to about 0.7 total mg of colchicine, a salt thereof, and/or any combination thereof.
 24. The method of claim 23, wherein the atherosclerotic vascular disease is a coronary disease.
 25. The method of claim 24, wherein the coronary disease is a clinically stable coronary disease.
 26. The method of claim 23, wherein the composition reduces or prevents cholesterol crystal induced inflammation within atherosclerotic plaques.
 27. The method of claim 23, wherein the composition is formulated in a daily dosage for administration once per day.
 28. The method of claim 23, wherein the composition is formulated for administration orally, topically, parenterally, intraorbitally, ophthalmically, intraventricularly, intracranially, intracapsularly, intraspinally, intracisternally, intraperitoneally, buccally, rectally, vaginally, intranasally, or by aerosol administration, and/or inhalation spray, or via an implanted reservoir.
 29. The method of claim 23, wherein the composition is in the form of a tablet, capsule, liquid dose, gel, or powder.
 30. The method of claim 23, wherein the tablet is an immediate release tablet.
 31. The method of claim 23, wherein the composition comprises about 0.6 mg of colchicine, a salt thereof, or any combination thereof.
 32. A method for treating and/or reducing the risk of cholesterol crystal induced inflammation within atherosclerotic plaques in a subject who has been diagnosed with atherosclerotic vascular disease, which comprises administering 0.5 mg to 0.6 mg of colchicine, a pharmaceutically acceptable salt of colchicine, or any combination thereof. 